Role of N-2-Hydroxy-Ethyl-Piperazine-N&#39;-2-Ethane Sulfonic Acid (HEPES) in Pain Control and Reversal of Demyelinization Injury

ABSTRACT

Compositions and therapeutic uses of HEPES and derivatives in the treatment of pain associated with cancers and side-effects including post-chemotherapy cognitive impairment are disclosed herein. HEPES is also used to treat neurodegenerative and neurological diseases, demyelinization injuries, and side-effects and withdrawal symptoms associated with benzodiazepines, anti-depressants, and other neurological agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation patent application of U.S.patent application Ser. No. 15/725,007 filed on Oct. 4, 2017 andentitled “Role of N-2-Hydroxy-Ethyl-Piperazine-N′-2-Ethane Sulfonic Acid(HEPES) in Pain Control and Reversal of Demyelinization Injury,” whichis a continuation patent application of U.S. patent application Ser. No.14/481,582 filed on Sep. 9, 2014 and entitled “Role ofN-2-Hydroxy-Ethyl-Piperazine-N′-2-Ethane Sulfonic Acid (HEPES) in PainControl and Reversal of Demyelinization Injury,” now U.S. Pat. No.9,867,820 issued on Jan. 16, 2018; which is a continuation patentapplication of U.S. patent application Ser. No. 12/885,404 filed on Sep.17, 2010 and entitled “Role of N-2-Hydroxy-Ethyl-Piperazine-N′-2-EthaneSulfonic Acid (HEPES) in Pain Control and Reversal of DemyelinizationInjury,” now U.S. Pat. No. 8,883,855 issued on Nov. 11, 2014, whichclaims priority to U.S. Provisional Application Ser. No. 61/243,464filed Sep. 17, 2009, the entire contents of which are incorporatedherein by reference.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC

None.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of pain controlpost-chemotherapy, and more particularly, to compositions and use ofN-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) as paincontrol agents and to reverse demyelinization injury.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with compositions and therapeutic uses of piperazine basedcompounds and their derivatives.

U.S. Pat. No. 5,248,680 issued to Bloomfield (1993) describeszwitterionic compounds selected from, taurine (2-aminoethanesulphonicacid), 2(N-morpholino)ethanesulphonic acid (IVIES),N-(2-acetamido)iminodiacetic acid (ADA),piperazine-N,N′bis(2-ethanesulphonic acid (PIPES),N-(2-acetamido)-2-aminoethanesulphonic acid (ACES),N,N-bis(2-hydroxyethyl)-2-aminoethanesulphonic acid (BES),3-(N-morpholino)propanesulphonic (MOPS),N—N-[tris(hydroxymethyl)-methyl]-2-aminoethanesulphonic acid (TES),N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid (HEPES),N-2-hydroxyethylpiperazine-N′3-propanesulphonic acid (H)EPPS),2-(cyclohexylamino)ethanesulphonic acid (CHES) or3-(cyclohexylamino)propanesulphonic acid (CAPS), and their N-haloderivatives that can be used separately or in combination in thetreatment of related clinical conditions by stimulating myeloperoxidaseactivity, which in turn stimulates hypochlorous acid production in vivo,which leads inter alia to enhanced leukotriene inactivation.

U.S. Pat. No. 5,716,959 issued to Theodore and Van Zandt (1998)discloses a substituted piperazine zwitterion composition containing,for example, as an active ingredient, HEPES (N-2Hydroxyethylpiperazine-N′-2 Ethane Sulfonic Acid), and method useful fortreatment of cancer, autoimmune, arthritis and other mammalian diseases.

U.S. Patent Application No. 20090149464 (Sergeant et al., 2009)describes the use of 1,4-bis(3-aminoalkyl)piperazine derivatives for themanufacture of a pharmaceutical composition intended for the treatmentof neurodegenerative diseases, related neurodegenerative diseases,developmental diseases or cancer. The instant invention is also directedto some specific 1,4-bis(3-aminoalkyl)piperazine derivatives andpharmaceutical composition including them.

SUMMARY OF THE INVENTION

The present invention describes the use of HEPES and derivatives thereofas an analgesic agent, an antitumor agent, for the stabilization ofcellular, especially neuronal membranes, and for the reversal ofdemyelinization injury. Separate embodiments of the present inventiondetail the use of HEPES in treating neurodegenerative, demyelination,neurological diseases, and also for treating neuropsychiatric disorderslike Tourette's syndrome. Compositions of HEPES as described herein arealso used to treat withdrawal symptoms, side-effects or both followingtreatment with anti-depressants and selective serotonin inhibitors(SSRI). HEPES is also used as an analgesic agent to treat painassociated with one or more cancers and for side-effectspost-chemotherapy including post-chemotherapy cognitive impairment.

In one embodiment the present invention discloses a pharmaceuticalcomposition for treating withdrawal symptoms, side-effects or bothfollowing treatment with anti-depressants, selective serotonininhibitors (SSRI), or other neurological agents in a subject comprising,N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers in an amount sufficient to treatwithdrawal symptoms, side-effects or both following treatment with oneor more anti-depressants, one or more selective serotonin inhibitors(SSRI), or other neurological agents. The composition of the presentinvention may optionally contain one or more excipients, diluents,extended or controlled release agents, coloring agents, preservatives orany combinations thereof. In one aspect the HEPES is dissolved insterile water for injection for oral, subcutaneous, parenteral,intravenous, peritoneal, or intramuscular administration and isadministered once daily on a body weight basis at 10-100 mg/kg. Inanother aspect the anti-depressants are selected from the groupconsisting of benzodiazepines, SSRIs, Serotonin-norepinephrine reuptakeinhibitors (SNRIs), Noradrenergic and specific serotonergicantidepressants (NaSSAs), Norepinephrine (noradrenaline) reuptakeinhibitors (NRIs), Norepinephrine-dopamine reuptake inhibitors (NDRIs),Selective serotonin reuptake enhancers (SSREs), Melatonergic agonists,Tricyclic antidepressants (TCAs), and Monoamine oxidase inhibitor(MAOIs) and the SSRIs comprise citalopram, escitalopram, fluoxetine,fluvoxamine, paroxetine, sertraline, zimelidine or any combinationsthereof.

In a related embodiment the present invention describes a method oftreating withdrawal symptoms, side-effects or both following treatmentwith anti-depressants, selective serotonin inhibitors (SSRI), or otherneurological agents in a subject in a human subject comprising the stepsof: identifying a subject in need for treatment against the withdrawalsymptoms, side-effects or both following treatment withanti-depressants, selective serotonin inhibitors (SSRI), or otherneurological agents and administering a pharmaceutical compositioncomprising N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid(HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers once daily at adosage of 10-100 mg/kg of body weight, wherein the pharmaceuticalcomposition is administered orally, subcutaneously, parenterally,intravenously, peritoneally, or intramuscularly. In one aspect theanti-depressant comprises benzodiazepines or derivatives thereof.

In another embodiment the present invention described a pharmaceuticalcomposition for treating one or more neurodegenerative diseases,treating one or more demyelination diseases or both in a subjectcomprising, N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid(HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers in an amountsufficient to treat the one or more neurodegenerative diseases, the oneor more demyelination diseases or both and one or more optionalexcipients, diluents, extended or controlled release agents, coloringagents, preservatives or any combinations thereof. In one aspect the oneor more demyelination diseases comprise multiple sclerosis, transversemyelitis, Devic's disease, progressive multifocal leukoencephalopathy,optic neuritis, Leukodystrophies, Guillain-Barré syndrome,Charcot-Marie-Tooth Disease or any combinations thereof. In anotheraspect the one or more neurodegenerative diseases comprise Parkinson'sdisease, Alper's disease, Alzheimer's disease, Lou Gehrig's DiseaseCorticobasal degeneration, Creutzfeldt-Jakob disease, Frontotemporallobar degeneration Huntington's disease, Krabbe's disease, MultipleSystem Atrophy, Multiple sclerosis, Pick's disease, Primary lateralsclerosis, Progressive Supranuclear Palsy, Refsum's disease, Sandhoffdisease, Schilder's disease, Spinal muscular atrophy,Steele-Richardson-Olszewski disease or any combinations thereof. Inspecific aspects the demyelinating disease is Multiple Sclerosis and theneurodegenerative disease is Parkinson's disease. In yet another aspectthe HEPES is dissolved in sterile water for injection for oral,subcutaneous, parenteral, intravenous, peritoneal, or intramuscularadministration and the composition is administered once daily on a bodyweight basis at 10-100 mg/kg and treats the one or more demyelinationdiseases by restoring, repairing, and/or regenerating a myelin sheath.

In yet another embodiment the present invention describes a method oftreating one or more neurodegenerative diseases, treating one or moredemyelination diseases or both in a human subject comprising the stepsof: (i) identifying a subject in need for treatment against the one ormore neurodegenerative diseases, treating one or more demyelinationdiseases or both and (ii) administering a pharmaceutical compositioncomprising N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid(HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers once daily at adosage of 10-100 mg/kg of body weight, wherein the pharmaceuticalcomposition is administered orally, subcutaneously, parenterally,intravenously, peritoneally, or intramuscularly. In specific aspects ofthe method of the present invention the demyelinating disease isMultiple Sclerosis and the neurodegenerative disease is Parkinson'sdisease and the composition treats the one or more demyelinationdiseases by restoring, repairing, and/or regenerating a myelin sheath.

Another embodiment of the present invention relates to a pharmaceuticalcomposition for treating symptoms associated with one or moreneurological diseases, one or more neuropsychiatric disorders or both ina subject comprising, N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonicacid (HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers in an amountsufficient to treat the one or more neurodegenerative diseases, the oneor more demyelination diseases or both. The composition as described inthe present invention may optionally contain one or more excipients,diluents, extended or controlled release agents, coloring agents,preservatives or any combinations thereof. In one aspect the one or moreneurological or neuropsychiatric disorders comprise cerebral palsy,Tourette's syndrome, choreia, athetosis, bipolar disorder, schizophreniaor any combinations thereof. In another aspect the HEPES is dissolved insterile water for injection for oral, subcutaneous, parenteral,intravenous, peritoneal, or intramuscular administration. In yet anotheraspect the composition is administered once daily on a body weight basisat 10-100 mg/kg.

In one embodiment the present invention details a method for treatingsymptoms associated one or more neurological diseases, one or moreneuropsychiatric disorders or both in a human subject comprising thesteps of: identifying a subject in need for treatment against thesymptoms associated with the one or more neurological diseases, the oneor more neuropsychiatric disorders or both and administering apharmaceutical composition comprisingN-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers once daily at a dosage of 10-100mg/kg of body weight, wherein the pharmaceutical composition isadministered orally, subcutaneously, parenterally, intravenously,peritoneally, or intramuscularly. In one aspect of the method of thepresent invention the neurological disease is cerebral palsy, choreia,or athetosis and the neuropsychiatric disorder is Tourette's syndrome.

One embodiment of the present invention discloses a pharmaceuticalcomposition for treating pain associated with a cancer, side-effectsfollowing cancer treatment including post-chemotherapy cognitiveimpairment or both in a subject comprising:N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers in an amount sufficient to treatthe pain associated with the cancer, side-effects following the cancertreatment including post-chemotherapy cognitive impairment or both andone or more optional excipients, diluents, extended or controlledrelease agents, coloring agents, preservatives or any combinationsthereof. In one aspect the composition is used to treat pain associatedwith pancreatic cancer, breast cancer, colorectal cancer, ovariancancer, lung cancer, cervical cancer, gastric cancer, liver cancer,melanomas, brain tumors, multiple myeloma, prostate cancer, and bladdercancer. In another aspect the composition is used to treatpost-chemotherapy cognitive impairment following a breast cancertreatment. In yet another aspect the HEPES is dissolved in sterile waterfor injection for oral, subcutaneous, parenteral, intravenous,peritoneal, or intramuscular administration and is administered oncedaily on a body weight basis at 10-100 mg/kg.

In a related embodiment the present invention discloses a method oftreating pain associated with a cancer, side-effects following cancertreatment including post-chemotherapy cognitive impairment or both in ahuman subject comprising the steps of: (i) identifying a subject in needfor treatment against the pain associated with the cancer, side-effectsfollowing cancer treatment including post-chemotherapy cognitiveimpairment or both and (ii) administering a pharmaceutical compositioncomprising N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid(HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers once daily at adosage of 10-100 mg/kg of body weight, wherein the pharmaceuticalcomposition is administered orally, subcutaneously, parenterally,intravenously, peritoneally, or intramuscularly. In specific aspects thecomposition is used to pain associated with a pancreatic cancer and totreat post-chemotherapy cognitive impairment following a breast cancertreatment.

In one embodiment the present invention describes a pharmaceuticalcomposition for treating pancreatic cancer in a subject comprising:N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers in an amount sufficient to treatthe pancreatic cancer and one or more optional excipients, diluents,extended or controlled release agents, coloring agents, preservatives orany combinations thereof.

In another embodiment the present invention is a method of treatingpancreatic cancer in a human subject comprising the steps of:identifying a subject in need for treatment against the pancreaticcancer and administering a pharmaceutical composition comprisingN-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers once daily at a dosage of 10-100mg/kg of body weight, wherein the pharmaceutical composition isadministered orally, subcutaneously, parenterally, intravenously,peritoneally, or intramuscularly.

BRIEF DESCRIPTION OF THE DRAWINGS

None.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

The term “HEPES” as used in various embodiments of the present inventionrefers to N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid(C₈H₁₈N₂O₄S).

The term “withdrawal symptoms” as used herein is intended to includethose symptoms known to those skilled in the art attendant upon forceddiscontinuation of ingestion of a narcotic substance or a drug, andincludes vomiting, severe muscle spasms, agitation, lacramation from thenose and eyes, uncontrollable urination, nausea, and, in severe cases,convulsions, respiratory failure, and cardiac arrest.

The term “neurodegenerative disease” (or “neurological disease”) as usedherein refers to a disease or disorder of the nervous system,particularly involving the brain, that manifests with symptomscharacteristic of brain or nerve dysfunction, e.g., short-term orlong-term memory lapse or defects, dementia, cognition defects, balanceand coordination problems, and emotional and behavioral deficiencies.

The term “demyelinating disease” refers to any pathological process thatresults in the degradation or loss of the myelin sheath surrounding anaxon including, but not limited to, Multiple Sclerosis andGuillain-Barre syndrome. As used herein, the term “Multiple Sclerosis”refers to a demyelinating disorder of the central nervous systemcharacterized, anatomically, by sclerotic plaques in the brain andspinal cord producing symptoms including (but not limited to) visualloss, diplopia, nystagmus, dysarthria, weakness, paresthesias, andbladder abnormalities.

As used herein, the term “neuropsychiatric disorder” refers to a diseasehaving a pathophysiological component of attenuated NMDAreceptor-mediated neurotransmission. Examples of such disorders includeschizophrenia, Alzheimer's disease, autism, depression, benignforgetfulness, childhood learning disorders, closed head injury, andattention deficit disorder.

The term “cancer” as used herein refers to a cellular disordercharacterized by uncontrolled or disregulated cell proliferation,decreased cellular differentiation, inappropriate ability to invadesurrounding tissue, and/or ability to establish new growth at ectopicsites. The term also includes, but is not limited to, solid tumors andblood borne tumors. The term “cancer” encompasses diseases of skin,tissues, organs, bone, cartilage, blood, and vessels and includesprimary and metastatic cancers. The term “chemotherapy” as used hereinis defined as the treatment of disease with chemical substances. Usedherein chemotherapy refers to application of anti-neoplastic chemicalsto an individual with cancer. The goal of chemotherapy is selectivetoxicity to cancer cells.

As used herein the terms “administration of” or “administering a”compound refers to providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount”indicates that the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers to the treatmentof the mentioned conditions, particularly in a patient who demonstratessymptoms of the disease or disorder.

The term “excipients”, as used herein, is intended to include one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a human subject.Some examples of substances which can serve as excipients include sugarssuch as lactose, glucose and sucrose; starches such as corn-starch andpotato starch; cellulose and its derivatives such as sodiumcarboxymethylcellulose, ethylcellulose, cellulose acetate; powderedtragacanth; malt; gelatin; talc; stearic acid; magnesium stearate;calcium sulfate; vegetable oils such as peanut oil, cottonseed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, mannitol, and polyethyleneglycol; agar; and alginic acid; as well as other non-toxic compatiblesubstances used in pharmaceutical formulations. Wetting agents andlubricants such as sodium lauryl sulfate, as well as coloring agents,flavoring agents, sweetening agents (including nonnutritive sweetenerssuch as aspartame and saccharin), tableting agents, stabilizers,antioxidants, cooling agents, and preservatives, can also be present.

By “pharmaceutically acceptable” it is to be understood that thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not be deleterious to the recipientthereof.

The present invention uses a N-2-Hydroxy-ethyl-piperazine-N′-2-ethanesulfonic acid commercially known as “HEPES” is a zwitterionic moleculecommonly and widely used as a buffer in cell cultures of both animal andhuman origin. Studies have demonstrated that HEPES has the leastcytotoxicity of all the known buffers. HEPES is a piperazine-basedzwitterionic molecule. Piperazine compounds are derived from thephenothiazines. Phenothiazines have been approved by the FDA asanti-anxiety and anti-psychotic agents. Non-zwitterionic piperazinecompounds have been approved by the FDA as antihelminthic agents. Otherpiperazine-based molecules are approved as food additives. Mechanisms ofaction of HEPES include the following:

-   -   (i) Analgesic activity, possibly related to prolonged        anti-anandamide action, without the significant side-effects in        contrast to the opiates;    -   (ii) Anti-tumor activity possibly related to mechanisms        previously found with promethazine;    -   (iii) Stabilization of cellular, especially neuronal membranes,        possibly by regulation of various ion channels; and    -   (iv) Reversal of demyelination injury.

The product, HEPES, is produced in ultra-pure form and is available fromGIBCOL Technologies, Inc. The product is administered on a body weightbasis with the determined minimal effective daily dosage of 70-75 mg/kg.The material may be safely given either by oral or parenteral routes.The present inventors have on a number of occasions observed that, themedication can be taken by both routes without any significantside-effects. The administered product is prepared by a compoundingpharmacist, with the dosage of each patient recipient beingindividualized.

Clinical Cases of Various Neurological Disorders

Demyelinating Diseases:

Myelin sheaths, which cover many nerve fibers, are composed oflipoprotein layers formed in early life. Myelin formed by theoligodendroglia in the CNS differ chemically and immunologically fromthat formed by the Schwann cells peripherally, but both types serve thesame function of promoting transmission of a neural impulse along theaxon.

1. Multiple Sclerosis: Many congenital metabolic disorders may result indefective myelin sheath formation. Demyelination in later life is afeature of many neurological disorders, which may arise from a plethoraof causes, e.g., damage from local injury, ischemia, toxic agents, ormetabolic disorders. Extensive myelin loss is often followed by axonaldegeneration and often by cell body degeneration, both of which may beirreversible.

Fortunately, spontaneous remyelination may occur in many instances, andrepair, regeneration, and complete recovery may occur with rapidrestoration of neural functions in some cases, while in others, there isunrelenting progression and worsening neural injury, with complete lossof physiological functioning. Central demyelination (i.e., of the spinalcord, brain, or optic nerves) is the predominant finding in the primarydemyelinating diseases, for which there is no known etiology. The mostwell-known condition is Multiple Sclerosis (MS). The exacerbations andremissions of symptoms of MS serve as the prime example of injury andrecovery. Symptoms of MS are extremely varied and diverse and may beconsidered in several categories: (i) Mental—apathy, poor judgment,depression, emotional lability, (ii) Cranial Nerve Dysfunction—3^(rd),4^(th), and 6^(th) cranial nerve problems often associated with mildnystagmus with fatigue, (iii) Sensory Neural Function—diminishedposition sense, multiple paresthesias especially involving theextremities, lateral trunk, and sides of the face, (iv) Motor NeuralFunction—diminished superficial reflexes, increased, oftensignificantly, deep tendon reflexes and Babinskis, intention tremor, andgeneralized muscular weakness, (iv) Autonomic Neural Function—urinaryurgency and hesitation, often slight incontinence, constipation.

Example 1

B.F. is a 42-year old public elementary school teacher, who wasdiagnosed with MS when she was 35. She has had significant recurringsymptomatology every 4-6 months with different symptom profiles,suggestive of variable sites of involvement.

Mentally, she often experienced periods of lack of concentration andfollow-through of immediate projects, generalized muscular stiffness andlack of fine motor coordination with episodes of lurching gait andimbalance. Very bothersome was her manual discoordination whichadversely influenced her writing on the chalk board. Indeed, thesymptoms were so frequent that her teaching contract was not renewed.She subsequently obtained employment at an academically excellent smallEpiscopal school where the classes were small and the stress level wasconsiderably less compared with the public school system.

Despite these changes of venue, she had more frequent exacerbations andremissions and experienced multiple medication programs with her veryconcerned neurologist physician. She continued to use block letters onthe blackboard rather than cursive black-board writing as a form ofcommunicating with her students.

After a particularly severe episode of problems, she completely lost theability to write (e.g., writing a payment check) owing to the loss ofmanual sensory function and erratic motor movements. The presentinventors were asked to see her by the school administrator, who servedas her friend and confidant. She was started on HEPES at a dosage of5,000 mg (5 tsp) daily—2 tsp with breakfast, 1 tsp mid-afternoon, and 2tsp at bedtime. After only three days of treatment she regained theability to write cursively and sign her name in a legible fashion. Shehas been continued on the oral medication and has maintained her motorfunction as well as being free of new exacerbations.

2. Cerebral Palsy: The term cerebral palsy (CP) identifies children withnon-progressive spasticity, ataxia, or involuntary movements. Between0.1-0.2% of children have CP symptoms, while up to 1% of prematurenewborns or those small for gestational age are affected. The causeshave been difficult to uncover but prematurity, in-utero disorders,neonatal jaundice and perinatal asphyxia are thought to play a role withbirth trauma and perinatal asphyxia or kernicterus of special interest.CP syndromes are grouped into four main categories, spastic, athetoid,ataxia, and mixed forms. Spastic paraplegia is especially common afterpremature birth, spastic quadriplegia after perinatal sepsis, andathetoid and dystonic forms after perinatal asphyxia or kernicterus.Spastic cases occur in about 70% of cases. The spasticity is due toupper motor neurone involvement with mild to severe affections of motorfunctioning, e.g., hemiplegia, paraplegia, quadriplegia, or diplegia. Itmay take up to two years to make a definitive diagnosis of CP type.Treatments include physical therapy, occupational therapy, bracing,orthopedic surgery, and speech training. As with all chronicallyhandicapped children, parents need assistance and guidance inunderstanding the child's status and potential and in relieving theirown feelings.

Example 2

M.S. is a 17-year old boy of Chinese extraction, whose birthing wasextremely difficult, and very probably associated with some degree ofneonatal asphyxia, although this was not seriously reflected in theApgar Score. M.S. has had superb medical care all his life long withloving and supportive parents able to provide recommended therapies.

Despite the abundance of treatment programs, it required nearly fiveyears for M.S. to walk slowly in an unassisted manner. Amazingly, hisspeech pattern and intellectual capabilities were remarkably functional.A major problem was his significant dysfunction with motor skills in hishands. M.S. was given an oral dosage of HEPES of 5,000 mg daily (2 tspswith breakfast, 1 tsp mid-afternoon, and 2 tsps at bedtime). After threeweeks his walking pattern showed considerable improvement withsignificant reduction in ataxic characteristics, the movement andcontrol of his hands and especially his fingers improved to the pointwhere he could selectively (upon oral command) depress the correct keyon the computer. After 8 months of therapy, his walking and manualskills have improved to 85% of normal. He became devoted to spendingseveral hours daily on the computer and the amount of knowledge he hasacquired and retained is, indeed, phenomenal. The change in this youngman has been outstanding and truly gratifying to his parents, hissiblings, and especially his physicians.

3. Post Chemotherapy Cognitive Impairment (PCCI): Post chemotherapycognitive impairment (also known as chemotherapy-induced cognitivedysfunction, chemo brain or chemo brain fog describes the cognitiveimpairment, which can result from chemotherapy treatment. Approximately30-40% of persons who undergo chemotherapy experience some level ofPCCI. The phenomenon initially came to light because of the large numberof breast cancer survivors who complained of memory, fluency, and othercognitive liabilities that impeded their ability to function as they hadprior to chemotherapy. In most cases there is no known way of reducingthe effects of chemotherapeutic agents related to taxanes, thalidomideand platinum-based compounds, but cognizance needs to be taken of theinnate ability of the nerves to repair themselves, at least to someextent, to metabolize and excrete these compounds, to change thepermeability of the blood-brain barrier, reverse the damage to DNAincluding the shortening of telomeres and cellular oxidative stress.Other theories suggest vascular injury, inflammation, autoimmunity,anemia and the presence of epsilon-4-version of the apolipoprotein-Egene. The compared systems most affected by chemotherapy drugs includevisual and semantic memory, attention and motor coordination. Theseeffects can impair the patient's ability to intelligently understand andmake decisions regarding treatment, performance in school or employment,and reduce significantly the quality of life.

Cognitive dysfunction (or brain fog) is usually associated with poormental function, especially regarding concepts, words, memories, and ischaracterized by confusion, forgetfulness, difficulty in concentration,and maintenance of focus. Sleep patterns are often disturbed anddefective REM (dream) sleep may result in serious depressive disorders.One nurse's experience: “One of” the first things that makes us realizethat there is something wrong with us is the inability to performintellectually like we once did. We seemingly accept the increasingpain, muscle spasms, the insomnia, but when we keep forgetting our ownphone number, red flags go up. We lose things—misplace others—on a routewe know, we get lost—we forget where we're going—shopping lists losetheir importance because we keep forgetting to bring them—we lose ourcar in parking lots time and time again—we come home from shopping andrealize we bought the exact same things the day before. We forgetfriends' names. We stop in mid-conversation because we've forgotten whatwe were talking about. We start using gadgets and date books in order tokeep track of our normal to-do list. If we handle our own checkbook, wegradually have more and more trouble with it. Even taking a shower is amajor effort because we don't remember whether we've rinsed the shampooout of our hair—we lose the washcloth—we drop everything—we forgetwhether we rinsed all those hard-to-reach areas. What were oncefunctions we handled without thought, we now need to consciously reviewevery aspect of the process before it occurs. We laugh about it. Welearn to “cover” the errors with laughter. But we're embarrassed andsilently questioning our own sanity. We worry about brain tumors andAlzheimer's because we know the problem is far more extensive than otherpeople are seeing. As one colleague said, “I can no longer rely on me!”So we joke about it with each other. This is not everyday forgetfulnessthat everyone experiences from time to time. This is a 24-hour, sevendays-a-week continual struggle to appear and act normally. It's beenproven by SPECT and PET scans of the brain. It really IS all in ourheads—and it's real.” The multiplicity of “treatments” for brain fogindicates the deficit of information which resides with the medicalprofessionals. Suggested therapies include: antioxidants, cognitivebehavior modification, erythropoietin injections, stimulant drugs,hypnosis, thyroid replacement therapy, neurofeedback treatments.

Example 3

KL is a 45-year old woman who, prior to her diagnosis of breast cancer,has been in charge of the family business involving a host of necessarytransactions, including maintenance of financial records and taxliabilities.

Post chemotherapy she had profound difficulty remembering what day itwas, what time it was, had she taken her morning bath, what to cook forany meal, forgetfulness as to daily chores, transporting her children toschool-sponsored events, suddenly breaking telephone conversations withher concerned mother without any recall of the action.

The major deficit business-wise was the inability to perform simplemathematical calculations. These short-comings resulted in taxconsequences of which she was totally unaware. Chronic, unrelentingphysical fatigue was creating a serious impediment in the familyconstellation especially with her husband, who did not realize what washappening. He thought she “was going bonkers!”

Her mother inquired as to what could be done to alleviate the rapidlydeteriorating family problems. A trial on HEPES was recommended as thesymptoms were, at least in part, related to demyelination. She wasstarted on oral HEPES, 5,000 mg daily in divided doses. Within threedays she indicated that the “cloud” had “risen.” It was still there, buther cognitive abilities, especially as to current events and herobligations in achieving her goals, were improved. Within a few moredays, the cloud was ascending higher, and after a month the “cloud” wasgone. She continues to show improvement in a gratifying manner.

Parkinson's Disease: Parkinson's Disease is the 4^(th) most commonneurodegenerative disorder of the elderly, affecting about 1% of those65 years of age and older and 0.4% of those forty years and older. Meanonset is 57 years, but may begin in childhood and adolescence (juvenileparkinsonism). There are approximately 50,000 new cases diagnosedannually. The pigmented neurons of the substantia nigra, locuscaeruleus, and other brain stem dopaminergic cell groups are lost, dueto an undefined cause.

Symptomatically, in 50-80% of patients, the disease begins insidiouslywith a resting 4-8 Hz pill-rolling tremor of one hand. The tremor ismaximal at rest, diminishes with movement, and is absent during sleep;it may be significantly enhanced with emotional tension and fatigue.Usually, the hands, arms, and legs are most affected, in that order, butthe jaw, tongue, and forehead and eyelids may be affected as well, whilethe voice remains unaffected.

In many patients, only rigidity occurs without frank tremors. As therigidity progresses and movements becomes slowed, decreased, anddifficult to initiate, muscular aches and sensations of fatigue increasesignificantly. The face becomes mask like with open mouth and diminishedclinking. Posture becomes stooped. Patients have difficulty initiatingwalking and the gait becomes shuffling with short steps, arms flexed tothe waist without any swing with stride. Steps inadvertently quicken andthe patient may break into a run to keep from falling (festination).Falls in various directions result from impaired postural reflexes.Speech becomes hypophonic with a monotonous, stuttering dysarthria.Depression is common.

Levo-dopa, the metabolic precursor of dopamine crosses the blood-brainbarrier into the basal ganglia where it is decarboxylated to formdopamine, replacing the deficient neurotransmitter. After 2-5 years oftreatment with this medication, more than 50% of patients begin toexperience fluctuations in their response to levodopa. Amantadine mayaugment the effects of levodopa and dopamine agonists (bromocriptine andpergolide) directly stimulate dopamine receptors in the basal ganglia.The ominous triad of the disease, side-effects of the anti-parkinsoniandrugs, and inactivity result in a significant degree of obstipation,which is unrelenting despite high fiber intake, psyllium, and stoolsofteners.

Example 4

F.S. is a 45-year old landscape technician, who has had Parkinsoniansymptoms since his late 30's. The family history is positive. He hasbeen tried on a variety of Parkinsonian medications, the beneficialactions of which seem to disappear within a few months.

His major complaint was significant muscle weakness and stiffness whichwas present to the degree that it significantly interfered with hisnursery/gardening activities. The hand tremor was present only to asmall degree, but the head tremors and tics were very prominent to thedegree that he would become nauseated if he kept his vision pinpointed.

He was placed on 5,000 mg of HEPES daily, in divided doses, and hismuscular fatigue, stiffness, and tics all disappeared within athree-week period. After another couple of weeks he said he felt like hewas before the diagnosis was made and was able to complete all of hislawn/garden service to clients in a timely manner.

Example 5

B.S. is a 83-year old male who has had Parkinsonian symptoms since hewas 75 years old. He was placed on levo-dopa with gradual increases tosix per day along with large doses of Mirapex and polyethylene glycolfor his problem with constipation. His constipation was really quiteintractable with abdominal distention and protrusion, nausea andvomiting. Also very worrisome was his diminished deglutitionary activityand tongue biting with oral bleeding. He was unable to stand withoutassistance and his hesitant walk favored the festinative aspects. Owingto the significance of his disease, he was placed on 6,000 mg of HEPESdaily in divided doses, which within three days obviated his swallowingdifficulties and abrogated his tongue biting. Over time the daily dosageof levodopa was reduced from the prescribed 6 per day to 2 per day towhich a small dose of the dopamine agonist, bromocriptine, was addedwith singularly beneficial results. His condition improved to the extentthat he was again able to drive himself to the store, buy gasoline, andeat out. Most, most gratifying, indeed!

He was placed on an active bowel treatment program with good resultswhich, when required was supplemented with an enema q.o.d. He continuedto be monitored closely. His energy level has improved significantly,his facial mask has completely disappeared, and his quality of lifevastly improved.

Clinical Cases Based Upon Mechanism of Action of HEPES. Analgesic andAnti-tumor Activities of HEPES-Cancer of the Pancreas

Example 6

JWH, a 68-year old white male, who owned and operated a commercialheating and air-conditioning business, had enjoyed good health untilSeptember, 2005, when he developed symptoms of fatiguability andintermittent episodes of pain in the upper abdomen with referral throughto the back, suggestive of a pancreatic problem. The pain was notrelieved by passing bowel movements or any other maneuver. He was seenby his personal physician, who diagnosed Type II diabetes mellitus. Hewas placed on anti-diabetic medication and diet. No additional studiesrelated to the abdominal pain were carried out, even though they werepeculiar in a patient with diabetes. His diabetic state was undersatisfactory control with a few weeks, but the abdominal pain problempersisted.

The abdominal pains increased in intensity with new severe pains in themid-dorsal thoracic spine. In late December, 2005, he suffered anepisode of sudden, very intense pain in the spinal area, was seen in theemergency room, where the origin of his spinal pain was found to besecondary to bony metastases. He was hospitalized for work-up and wasfound to have primary pancreatic cancer with metastases to the liver,lungs, shoulders and thoracic spinal column. He underwent radiationtreatments for the thoracic lesions which eased, to a limited extent,the pain in this area.

In consultation with the patient ombudsmen group at M. D. AndersonHospital in Houston, Tex., the family was told that none of the currentstudy protocols were appropriate for his current condition of cancer ofthe pancreas with wide-spread metastases and such advanced disease. Hewas given 2-4 months to live. It was recommended that he be treated withpain protocols by the local institutions in the Dallas-Fort Worth area.He was treated by his personal physician who placed him on opiateanalgesics for pain control.

In February, 2006, his personal physician contacted the presentinventors concerning the possible addition of HEPES as he was receivingthe maximal level of opiate medication, which was not controlling thepain the patient was experiencing. In March, 2006, he was placed on adaily dosage of the product administered by intravenous infusion, whilecontinuing his maximum opiate analgesic medication. After 5 days ofadding the HEPES, his pain was completely controlled. During April, May,and June, 2006, his narcotic medication was slowly reduced owing to theplethora of narcotic-related side-effects (Table 1), with good paincontrol using about 25% of the maximum dosage of the opiate analgesics.

His quality of life improved significantly at this time. In July, 2006,he developed significant anorexia, probably secondary to the increasinglevels of endogenous TNF-alpha (cachectic factor). Dronabinol wasrecommended, but refused by the patient owing to the medication beingderived from marijuana. Thereafter, natural source inhibitors ofcachectic factor (Table 2) were recommended, but the patient refused totake any of these as he felt these might interfere with the paincontrol, which was acceptable. He was then offered parenteralnutritional support, which he declined.

His quality of life was reasonably good, and his condition was such thathe was able to take daily 30-minute walks in the mall, was able toattend his 50 year high school reunion in September, 2006, attended inOctober, 2006, a VIP high school parking lot dedicated to him, went to adance with his wife in early November, 2006, as well as a high schoolfootball game, and celebrated his 69^(th) birthday with the entirefamily.

From mid-November, 2006, he developed weakness associated with continuedweight loss, and from late November became bed-ridden. He continued tosuffer from cyctokine-induced (cachectic factor/TNF-alpha) anorexia,which resulted in almost complete inanition, with death ensuing on 19Dec. 2006. While the death certificate lists the cause of death ascancer of the pancreas, in truth the cause of death was terminalanorexia, inanition, and malnutrition, with more than 65 pound weighloss.

HEPES administration, however, was associated with improved paincontrol, reduction in the amount of opiate narcotic analgesia required,elimination of opiate side-effects, a significant anti-tumor effect withseveral additional months of quality living, which was very muchappreciated by the family constellation.

Stabilization of Neural Membranes.

Pediatric Autoimmune Neurological Disease Associated with Strep (PANDAS)

Example 7

HSW is an 8-year old boy referred to the present inventors by one of ourpediatric neurologists. Historically, at the age of three years, thisyoung boy contracted an infection caused by a very virulentstreptococcal micro-organism. It required three courses of antibiotictherapy before the symptoms abated, and apparent recovery took place.About 6-weeks later, he began having involuntary tics involving hishead, neck, and shoulders often with flailing arms. Initially, thesemovements were 10-15 per day. Over the next three months, the athetoticmovements increased to 1,300-1,500 per day.

TABLE 1 Side-effects of Opiate Analgesics Cardiovascular SystemHypotension Hypertension Bradycardia Tachycardia Palpitations PedalEdema Syncope Central Nervous System Agitation Sedation LightheadednessDizziness Tremors Seizures Paresthesias Gastrointestinal SystemXerostomia Anorexia Nausea Vomiting Biliary Tract Spasm ConstipationDiarrhea Ileus Intestinal Obstruction Elevated Liver Enzyme LevelsGenitourinary System Hesitation in Starting Urinary Stream Urinaryretention Antidiuretic Effect Decreased Libido Integumentary SystemFacial Flushing Primary Urticaria Rashes Musculoskeletal System MuscleRigidity Uncoordinated Muscular Movements Muscular Weakness Psyche MoodAlteration Euphoria Dreams Respiratory System Drug-induced Respiratorydepression leading CO₂ retention resulting in increased CSF pressure &increased ICP Dysphonia Laryngeal Spasms Sleep Patterns Insomnia 2⁰ ↑ICP Systemic Effects Drug Dependency Anaphylaxis Temperature RegulationDiaphoresis Chills Visual Disturbances Blurred Vision DiplopiaNystagamus Miosis

TABLE 2 Natural Source Inhibitors of Cachectic Factor (TNF-alpha)(Partial Listing) 1. Aspirin 2. Salicylic Acid 3. Docosahexaenoic Acid(DHA) 4. Eicosahenaenoic Acid (EPA) 5. Quercetin 6. Curcumin 7.Epigallocatechin Gallate 8. Capsaicin 9. Citrus Flavonoids 10. Narigin11. Epicatechin 12. Quinine 13. Colchicine 14. Anandamide 15. Morphine16. Resveratrol 17. Myricetin 18. Butylhydroxyacetate (BHA) 19. PGE₂ 20.Hydroquinone 21. Forskolin 22. Santamarin 23. Tetrahydropapaveralione24. 4-Hydroxy-2-noneal

The pediatric neurologists at numerous medical centers were consulted,with various medications prescribed, which, at best, decreased to aminimal degree the frequency of the movements, but which wereaccompanied by a number of undesirable side-effects. Over the next 5years, the parents consulted physicians at various famed medical centersin Scandinavia, Germany, Switzerland, Israel and England, all withoutany significant improvement. Just prior to his referral to us, he wasseen at the NIH, where a very thorough work-up was accomplished, butwhere the recommendation given the parents was that little could be doneor expected as most of the medications available world-wide had beentried without success.

HEPES was cautiously given daily to the youngster in graded intravenousdoses owing to the bewildering 1,300-1,500 athetotic movements present.At the end of the first week, having achieved the 70-75 mg/kg level ofHEPES administration, the frequency of athetotic movements had beenreduced to 10-15 per day. At the end of the second week on the IVproduct, there was a further reduction in the athetosis with 2-3movements per day.

The lad was then placed on oral medication at the same daily dosage.During the next three weeks, there were infrequent involuntary athetoidmovements triggered by emotional or stressful circumstances. The productwas then decreased gradually, with the boy now tic-free without anyproduct being given. It remains moot whether or not there will be arecurrence of the problem, but we are hopeful that the membranestabilization induced by the HEPES moiety will have a permanent curativeeffect. This response to HEPES has been considered to be more thanmiraculous by his parents and other family members, his referringneurologist, as well as the present inventors.

Benzodiazepine Withdrawal Symptoms

Example 8

MS is a 48-year old male, who was initially placed on benzodiazepinemedication for panic attacks which presented at age 11. He has been onvarious forms of medications constituting this group for more than threedecades. The dilemma which exists is that often the original conditionfor which the diazepines are prescribed are considered to be psychiatricin nature. When pain and neurological symptoms appear associated withwithdrawal, it is often misdiagnosed with additional medications givenwhich compounds the problem. These medications are recommended for shortterm treatment (4-6 weeks) only, but as with this patient, usage extendsover years. Pain manifestations associated with withdrawal from thesedrugs are shown in Table 3. One of the major withdrawal symptoms includeviolent repetitive “tics” which are considerably worsened with emotionalsituations and other stressors. Abnormal ideation often takes the formof bizarre thoughts as the functioning of the superego is markedimpaired. Thus, these patients do things which under normal conditionswould never contemplate, much less act out. As a result of thesefactors, our patient lost his successful business, his houses, and hisfamily comprised of his wife and three beautiful daughters, ages 14, 11,and 7. He walks with a hopping motion associated with bizarre flailingmovements of the shoulder and arms. On the internet are listings of morethan 300 withdrawal symptoms. The present inventors were consulted onthis patient to see if we could ameliorate his extreme pain problems.His neurologic examination was truly strange. One prominent feature wasa completely normal ability to dorsiflex his right foot with a 4+ inchelevation, but only a fraction of an inch with his left foot, which alsoshowed tense plantarflexion.

He was started on HEPES by the oral route. After four days on theproduct, a repeat neurologic examination should normal dorsiflexion ofhis left foot, equal to that of the right foot, a truly amazingobservation. With continued daily product at the 75 mg/kg dosage, he hasshown slow improvement manifest by a significant reduction in hisathetoid movements, improved gait, more cogent ideation, and significantrelief of his pain, which consisted of intense pain in his jaws andteeth, shoulder joints and muscles, precordial chest pain, and sharppains in the temples bilaterally. He will be closely monitored as to hiscondition with additional treatment.

In the United States it is estimated that there are between 5-6 millionpersons with similar histories, and another 2 million in the UnitedKingdom. If the use of HEPES can ameliorate these dreadful withdrawalsymptoms, it will prove to be a significant contribution to easing thedistress these patients continually undergo, as the HEPES product enjoysan enviable position of showing no side-effects.

TABLE 3 Pain Syndrome Sites Associated With Benzodiazepine withdrawal 1.Aching Jaws 2. Aching Joints 3. Aching Muscles 4. Back Pain 5. Breasts6. Burning Pain of Scalp, Neck, and Shoulders 7. Ear Aches, frequentlyrecurring 8. Headaches, often severe 9. Intense Jaw Pain 10. MuscularCramps and Spasms 11. Neuralgias 12. Paresthesias of the Scalp 13. VeryPainful Teeth 14. Chest Pain 15. Pain with breathing 16. Sharp ThrobbingPains in Temples 17. Throbbing Pains in Wrists 18. Severe AbdominalCramping Pain

Reversal of Demyelination Processes

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

CIDP is an autoimmune neuropathy that affects the peripheral motor andsensory nerves. The symptoms are of a slowly progressive numbness andtingling that usually starts in the feet, but later spreads to the legsand hands. The patients also complain of some weakness, again usuallystarting in the lower extremities, but soon involving the upperextremities as well. With further involvement of the sensory system,other modalities of sensations, such as balance, are affected and thepatients complain of inability to walk or maintain balance in the dark.There usually is not bowel or bladder involvement. On rare occasions,cranial nerves are involved and then the symptoms range from difficultyin deglutition to double vision with numbness involving the face.Cognitive skills are not affected by CIDP.

The diagnosis of CIDP is suspected with a history of progressivesensorimotor neuropathy. Physical examination consistent with distalsensory loss in the upper and lower extremities, in conjunction withmotor weakness that can be more proximal than distal supports theclinical diagnosis.

Patients may present with pain, numbness or weakness. One of the earlysigns is a patient who has to use their hands to go upstairs or risefrom the squatting position. Some have vasomotor symptoms likedifficulty in maintaining their blood pressure, burning sensations whichare misdiagnosed as Reflex Sympathetic Dystrophy. Even Complex RegionalPain Syndrome is more likely to be CIDP.

Once the diagnosis is confirmed, treatment with immunosuppressivemedications can be initiated. The first line of treatment remainshigh-dose immunoglobulin which is infused intravenously and tapered overtime depending on the patient's improved symptomatology. The use of IVIg has been shown in numerous studies to improve the symptoms of CIDP.

Example 9

MV is a 43 year old man who presents with a history of multipleallergies, infections (including viral meningitis/aseptic encephalitis),multiple episodes of antibiotic treatments, etc. He describes hisphysical status historically as follows: “I have been seriously illsince 1991 with progressive neurologic deficits, which culminated withsignificant loss of motor control in 1993. The condition wasmisdiagnosed as Multiple Sclerosis with negative findings on Mill.” Heinitially ambulated slowly with the use of a cane. In 1994 he wasparalyzed from the neck down. He was treated with Ig intravenously andrecovered over a period of weeks. Five months later, he experienced asimilar episode. This time the Ig therapy was only weakly helpful, andhe as treated with therapeutic plasma exchanges every two weeks.

He has recently been experiencing significant pains in his extremitiesand HEPES was started orally both for pain control and possiblereinforcement of any myelinating defects, as our medical colleagues inthe Netherlands have had significant success in reversing thedemyelination process. After three weeks on the daily oral product, hispain has been completely controlled, the weakness in his lowerextremities has almost completely resolved, and he has expressed hisfeeling that he feels better than he has for several years.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, AB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

REFERENCES

U.S. Pat. No. 5,248,680: Zwitterionic Compounds and Their N-HaloDerivatives for Use in the Treatment of Clinical Conditions.

U.S. Pat. No. 5,716,959: Method of Treating Disease with PiperazineZwitterion Compounds.

U.S. Patent Application No. 20090149464: Use of 1,4-bis (3-Aminoalkyl)Piperazine Derivatives in the Treatment of Neurodegenerative Diseases.

What is claimed is:
 1. A method of treating neurological impairmentcaused by one or more demyelination diseases, withdrawal symptoms,side-effects or both following treatment with anti-depressants,selective serotonin inhibitors (SSRI), or other neurological agents thatcause demyelination in a subject in a human subject comprising the stepsof: identifying a subject in need for treatment against the neurologicalimpairment caused by one or more demyelination diseases, withdrawalsymptoms, side-effects or both following treatment withanti-depressants, selective serotonin inhibitors (SSRI), or otherneurological agents that cause demyelination; and administering apharmaceutical composition comprisingN-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers once daily at a dosage of 10-100mg/kg of body weight, wherein the pharmaceutical composition isadministered orally, subcutaneously, parenterally, intravenously,peritoneally, or intramuscularly.
 2. The method of claim 1, wherein theanti-depressants are selected from the group consisting ofbenzodiazepines, SSRIs, Serotonin-norepinephrine reuptake inhibitors(SNRIs), Noradrenergic and specific serotonergic antidepressants(NaSSAs), Norepinephrine (noradrenaline) reuptake inhibitors (NRIs),Norepinephrine-dopamine reuptake inhibitors (NDRIs), Selective serotoninreuptake enhancers (SSREs), Melatonergic agonists, Tricyclicantidepressants (TCAs), and Monoamine oxidase inhibitor (MAOIs),citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,sertraline, zimelidine or any combinations thereof.
 3. The method ofclaim 1, wherein the HEPES is dissolved in sterile water for injectionfor oral, subcutaneous, parenteral, intravenous, peritoneal, orintramuscular administration.
 4. The method of claim 1, wherein thecomposition is administered once daily on a body weight basis at 10-100mg/kg.
 5. The method of claim 1, wherein the composition treats the oneor more demyelination diseases by restoring, repairing, and/orregenerating a myelin sheath.
 6. A pharmaceutical composition fortreating neurological impairment caused by one or more demyelinationdiseases, withdrawal symptoms, side-effects following treatment withanti-depressants, selective serotonin inhibitors (SSRI), or otherneurological agents that cause demyelination in a subject in a humansubject comprising: N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonicacid (HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers in an amountsufficient to treat the neurological impairment caused by one or moredemyelination diseases, withdrawal symptoms, side-effects followingtreatment with anti-depressants, selective serotonin inhibitors (SSRI),or other neurological agents that cause demyelination; and one or moreexcipients, diluents, extended or controlled release agents, coloringagents, preservatives or any combinations thereof.
 7. The composition ofclaim 6, wherein the one or more demyelination diseases comprisemultiple sclerosis, transverse myelitis, Devic's disease, progressivemultifocal leukoencephalopathy, optic neuritis, Leukodystrophies,Guillain-Barré syndrome, Charcot-Marie-Tooth Disease or any combinationsthereof.
 8. The composition of claim 6, wherein the one or moredemyelination diseases comprise Parkinson's disease, Alper's disease,Alzheimer's disease, Lou Gehrig's Disease Corticobasal degeneration,Creutzfeldt-Jakob disease, Frontotemporal lobar degenerationHuntington's disease, Krabbe's disease, Multiple System Atrophy,Multiple sclerosis, Pick's disease, Primary lateral sclerosis,Progressive Supranuclear Palsy, Refsum's disease, Sandhoff disease,Schilder's disease, Spinal muscular atrophy, Steele-Richardson-Olszewskidisease or any combinations thereof.
 9. The composition of claim 6,wherein the composition treats the one or more demyelination diseases byrestoring, repairing, and/or regenerating a myelin sheath.
 10. Thecomposition of claim 6, wherein the pharmaceutical composition fortreating symptoms associated with one or more demyelination disease in asubject comprising: N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonicacid (HEPES) and derivatives thereof dissolved in sterile water, buffer,saline or other pharmaceutically acceptable carriers in an amountsufficient to treat the one or more demyelination diseases; and one ormore excipients, diluents, extended or controlled release agents,coloring agents, preservatives or any combinations thereof.
 11. Thecomposition of claim 6, wherein the one or more demyelination diseasescomprise cerebral palsy, Tourette's syndrome, choreia, athetosis,bipolar disorder, schizophrenia or any combinations thereof.
 12. Apharmaceutical composition for treating pain associated with a cancer,side-effects following cancer treatment including post-chemotherapycognitive impairment caused by demyelination in a subject comprising:N-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers in an amount sufficient to treatthe pain associated with the cancer, side-effects following the cancertreatment including post-chemotherapy cognitive impairment or bothcaused by demyelination; and one or more excipients, diluents, extendedor controlled release agents, coloring agents, preservatives or anycombinations thereof.
 13. The composition of claim 12, wherein thecomposition is used to treat pain associated with pancreatic cancer,breast cancer, colorectal cancer, ovarian cancer, lung cancer, cervicalcancer, gastric cancer, liver cancer, melanomas, brain tumors, multiplemyeloma, prostate cancer, or bladder cancer.
 14. The composition ofclaim 12, wherein the composition is used to treat post-chemotherapycognitive impairment following a breast cancer treatment.
 15. Thecomposition of claim 12, wherein the HEPES is dissolved in sterile waterfor injection for oral, subcutaneous, parenteral, intravenous,peritoneal, or intramuscular administration.
 16. The composition ofclaim 12, wherein the composition is administered once daily on a bodyweight basis at 10-100 mg/kg.
 17. A method of treating pain associatedwith a cancer, side-effects following cancer treatment includingpost-chemotherapy cognitive impairment or both caused by demyelinationin a human subject comprising the steps of: identifying a subject inneed for treatment against the pain associated with the cancer,side-effects following cancer treatment including post-chemotherapycognitive impairment or both caused by demyelination; and administeringa pharmaceutical composition comprisingN-2-hydroxy-ethyl-piperazine-N′-2-ethane sulfonic acid (HEPES) andderivatives thereof dissolved in sterile water, buffer, saline or otherpharmaceutically acceptable carriers once daily at a dosage of 10-100mg/kg of body weight, wherein the pharmaceutical composition isadministered orally, subcutaneously, parenterally, intravenously,peritoneally, or intramuscularly.
 18. The method of claim 17, whereinthe composition is used to pain associated with a pancreatic cancer,breast cancer, colorectal cancer, ovarian cancer, lung cancer, cervicalcancer, gastric cancer, liver cancer, melanomas, brain tumors, multiplemyeloma, prostate cancer, or bladder cancer.
 19. The method of claim 17,wherein the composition is used to treat post-chemotherapy cognitiveimpairment following a breast cancer treatment.
 20. The method of claim17, wherein the HEPES is dissolved in sterile water for injection fororal, subcutaneous, parenteral, intravenous, peritoneal, orintramuscular administration.